Anita Rauch: Genetics of Hereditary Amyloidosis

Institut für Medizinische Genetik
Genetics of Hereditary
Amyloidosis
Anita Rauch
15.07.2014
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Institut für Medizinische Genetik
General characteristics of Hereditary Amyloidoses
 Autosomal dominant inheritance
 Variable expressivity and penetrance
 Genotype-Phenotype correlation
 Specific, amyloidogenic mutations
 Endemic hotspot mutations
15.07.2014
Anita Rauch
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Institut für Medizinische Genetik
Phenotypic grouping of hereditary amyloidoses
Neuropathic
(Polyneuropathy)
Non-Neuropathic
(Nephropathy)
• Transthyretin
• Apolipoprotein
A-I
• Gelsolin
•
•
•
•
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Anita Rauch
Fibrinogen A α
Lysozyme
Pyrin
Apolipoprotein
A-II
Cerebral
(Dementia)
• Presenilin 1
• Presenilin 2
• Amyloid
precursor
protein
• Cystatin C
• BRI
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Institut für Medizinische Genetik
Most common type:
Hereditary transthyretin amyloidosis
 TTR protein is produced primarily in the liver and is normally a
carrier for retinol binding protein
 peripheral sensory neuropathy, autonomic neuropathy, and/or
cardiomyopathy
Coelho T et al. Neurology 2012;79:785-792
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Anita Rauch
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Institut für Medizinische Genetik
TTR (Transthyretin): more than 100 known mutations
Sensori-motor peripheral neuropathy
Rarely cardiac involvement
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Anita Rauch
Senile cardiac amyloidosis
3-4% of African Americans are carriers
Bildquelle: http://www.alnylam.com/ Seite 5
Institut für Medizinische Genetik
Population endemic clinical variability:
Mean age of onset in Val30Met carriers
Portugues: 33.5 y
Swedish, French, or British much later
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Anita Rauch
Japan: 62.7 y
Ogawa / Arao: 40.1 y
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Institut für Medizinische Genetik
Genetic and environmental Modifiers
Variant c.416C>T (Thr119Met) has a protective effect on
amyloidogenesis in individuals who have the Val30Met mutation
Familial euthyroid hyperthyroxinemia is caused by benign
allelic variants in TTR, including Gly6Ser, Ala109Thr, Ala109Val,
and Thr119Met
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Anita Rauch
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Institut für Medizinische Genetik
Hereditary gelsolin amyloidosis
 “Finnish type” G654A or T
 G654A also reported in Portugal, Japan and Iran
 G654T reported in Denmark, Czech Rep. and France
 Actin-modulating protein enhancing cell migration
 Mutation unable to bind calcium ions  proteolysis  fibrils
 Typically corneal lattice dystrophy during early middle-age
 Rare cases homozygous mutations: rapid decline and renal failure
15.07.2014
Anita Rauch
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Institut für Medizinische Genetik
Proteinuria and progressive renal failure
 Fribrinogen Aalpha-chain amyloidosis

9 mutations, E526V most common
 Apolipoprotein AI amyloidosis

13 variants

Possible neurological, cardiac, hepatic dysfunction
 Apolipoprotein AII amyloidosis

4 mutations, earlier mean manifestation
 Lysozyme amyloidosis

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7 mutations, very slowly progressive
Anita Rauch
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Institut für Medizinische Genetik
Hereditary Early-onset Alzheimer Disease
 30-70 %PSEN1 (Presenilin 1)

~150 Mutationen
 10-15 % APP (Amyloid beta (A4) Precursor Protein)

>30 Mutationen
 5 % PSEN2 (Presenilin 2)

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~25 Mutationen
Anita Rauch
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Institut für Medizinische Genetik
“Next generation” genetic diagnostics
 Fast and efficient sequencing of gene panels
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Anita Rauch
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